Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells

Hepatocyte growth factor (HGF), a multifunctional cytokine of mesenchymal origin, activates the DNA binding of hypoxia inducible factor-1 (HIF-1) in the HepG2 cell line: the activated complex contained the inducible α subunit. An increased expression of HIF-1α (mRNA and nuclear protein levels) was o...

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Bibliographic Details
Published in:Carcinogenesis (New York) 2001-09, Vol.22 (9), p.1363-1371
Main Authors: Tacchini, Lorenza, Dansi, Paola, Matteucci, Emanuela, Desiderio, Maria Alfonsina
Format: Article
Language:English
Subjects:
Biological and medical sciences
c-Jun-N-terminal kinase/stress activated protein kinase
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Cysteine Endopeptidases - physiology
DNA, Neoplasm - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
DNA-Binding Proteins - physiology
Fundamental and applied biological sciences. Psychology
Gene Expression - drug effects
GSH
heme oxygenase
Heme Oxygenase (Decyclizing) - biosynthesis
Heme Oxygenase (Decyclizing) - genetics
hepatocyte growth factor
Hepatocyte Growth Factor - pharmacology
Hepatocyte Growth Factor - physiology
HGF
HIF-1
HIF-1 protein
Hox
HRE
Humans
hypoxia responsive element
hypoxia-inducible factor
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
JNK/SAPK
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
MAPK
mitogen activated protein kinase
Mitogen-Activated Protein Kinases - metabolism
Mitogen-Activated Protein Kinases - physiology
Molecular and cellular biology
Multienzyme Complexes - physiology
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Nuclear Proteins - physiology
Oct-1
octamer-1
Oxidation-Reduction
phosphatidylinositol 3-kinase
Phosphatidylinositol 3-Kinases - metabolism
Phosphatidylinositol 3-Kinases - physiology
PI3K
Proteasome Endopeptidase Complex
reactive oxygen species
Receptors, Cell Surface - biosynthesis
Receptors, Cell Surface - genetics
Receptors, Urokinase Plasminogen Activator
recombinant human HGF
reduced glutathione
rhHGF
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
ROS
Transcription Factors
Tumor Cells, Cultured
uPA
uPAR
urokinase plasminogen activator
urokinase receptor
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Summary:Hepatocyte growth factor (HGF), a multifunctional cytokine of mesenchymal origin, activates the DNA binding of hypoxia inducible factor-1 (HIF-1) in the HepG2 cell line: the activated complex contained the inducible α subunit. An increased expression of HIF-1α (mRNA and nuclear protein levels) was observed. To investigate the molecular basis of the HIF-1 response under this non-hypoxic condition, we evaluated first the expression of putative target genes. We found a time-dependent increase in steady-state mRNA levels of heme oxygenase and urokinase plasminogen activator at 4 h, followed by that of urokinase receptor at 10 h. The enhanced expression of these genes might confer the invasive phenotype, since HGF is a proliferative and scatter factor. Second, we examined some aspects of HIF-1 activity regulation in HGF-treated cells with the following findings: (i) the activation of HIF-1 DNA binding was prevented by proteasome blockade, probably because stabilization of the cytosolic α-subunit protein level is not sufficient to generate a functional form: also under these conditions nuclear protein level of HIF-1α did not increase; (ii) N-acetylcysteine, a free radical scavenger, strongly decreased HIF-1 activation suggesting a role of reactive oxygen species in this process; (iii) the thiol reducing agent dithiothreitol was ineffective. Third, consistent with these data, N-acetylcysteine reduced the stimulatory effect of HGF on stress kinase activities, while p42/44 mitogen activated kinase (MAPK) was unmodified, suggesting an involvement of c-Jun-N-terminal kinase (JNK) and p38 MAPK in HIF-1 activation. Finally, LY 294002 induced the blockade of phosphatidylinositol 3-kinase (PI3K), one of the principal transducers of HGF/Met receptor signalling, prevented the enhancement of HIF-1 DNA binding and JNK activity, but the inhibition of p42/44 MAPK phosphorylation with PD 98059 was ineffective. In conclusion, we suggest that HGF triggers a signal transduction cascade involving PI3K and ultimately activates HIF-1.
ISSN:0143-3334
1460-2180
1460-2180
DOI:10.1093/carcin/22.9.1363